1. Field of the Invention
This invention relates generally to artificial organs, and in particular to a both sides of a semipermeable membrane, low flow-by resistances “artificial gill” or “artificial lung”. The preferred embodiment, complementing liquid breathing through efficient CO2 removal, can be utilized for deep diving with normal sea level blood gases and without being threatened by the bends. Incorporated in a preferred embodiment, multi-artificial gills, “synthetic gill”, is a plurality of sequenced, diminishing membrane areas, diminishing volumes, increasing concentrations, two gills hemoglobin (Hgb) circuits that can be utilized for scavenging, concentrating, storing and delivering O2 from seawater in the case of a diver or from thin air in the case of a high altitude climber, and for dispelling CO2 from the diver's or climber's breathing cycle into water or air. An artificial gill utilized as an artificial lung, with the blood flowing through the comparatively large lumens of the identical hollow fibers, minimizes chaotic and stagnant blood flow which can engender clotting and embolization.
2. Discussion of the Prior Art
Both deep diving without being threatened by the bends and scavenging O2 from water to “swim like a fish” have fascinated minds for as long as humans have been able to dream. The bends have been circumvented only slightly by saturation diving, which is burdened by the logistics of extremely long decompression. Inert gases alchemy to replace N2 is of only marginal value. Liquid breathing's promise of sea level blood gases throughout a dive came a cropper over the inability of the blood borne CO2 to be adequately disposed of. Liquid breathing has found a clinical niche. Systems for oxygen extracting and concentrating from seawater or thin air continue to require large expenditures of energy and are suited for nuclear submarines, but probably not for free swimming divers. Alon Bodner of Israel engendered widespread publicity recently with his “Like a Fish” seawater centrifuge (U.S. Patent Publication No. 2004/0003811) in which lowered central pressures left by higher peripheral centrifugal pressures permit the central seawater to give up some of its dissolved air, including O2. Again, much energy is involved and this appears more applicable to submersibles rather than to divers. Waseda University in Tokyo has had a long running interest in artificial gills for oxygen scavenging and they seem to have gravitated away from other O2 carriers and toward Hgb as a first receiver of O2 across the membrane. They also manipulate their system with Inositol Hexaphosphate and energy consuming reciprocating temperatures. They have not recognized the utility of sequencing their Hgb in order to achieve stepwise seawater derived oxygen concentration (Matsuda, N, Sakai Technical Evaluation of Oxygen Transfer Rates of Fish Gills and Artificial Gills ASAIO J, 1999 293-298).
1. Deep Diving Artificial Gill
Liquid Breathing
Liquid breathing, on which much effort and large sums of money have been spent, does continue to hold the exciting promise that excessive concentrations of N2 or other inert “diving gases” in the blood might be avoided altogether, by flooding bodily air cavities (except bowel) with non compressible liquids, in order to eliminate altogether the highly compressed gases dissolving in blood, which is the root cause of the bends when ascent and decompression eventually take place. Would that all other breathing gases might just be replaced with O2, that could be rapidly consumed in metabolism. Unfortunately, there are low limits to the concentrations of O2 that tissues can withstand, without being “burned”, most notably in newborns whose loss of eyesight has been so proved.
Liquid breathing's great potential for O2 adequacy, despite the inefficiency of tidal breathing to adequately deliver viscous liquids in and out of end alveoli, stems from the capacity to dissolve high concentrations of O2 in the liquid proportional to the increasingly high pressures encountered during descent into the depths. Perfluorocarbon liquids (PFC) exhibit one-fourth the surface tension, sixteen times the oxygen solubility and three times the carbon dioxide solubility of water. Since oxygen and carbon dioxide dissolve so easily in this liquid, it is an excellent medium for carrying oxygen. Only a small proportion of the highly oxygenated breathing liquid needs to make it out into the twigs of the respiratory tree to achieve the required concentration of O2 in the blood. Delicate end alveolar membranes see only relatively normal concentrations of O2 and hence are not threatened by burn. One wishes that CO2 removal might be so easily accomplished.
The advantages of breathing a liquid while deep diving are undeniable. When a diver descends below 120 feet, even helium, substituted for nitrogen in diving, may be related with an effect called High Pressure Nervous Syndrome (HPNS).
Gas toxicity caused by oxygen has been shown to damage the lung and will vary with partial pressure above one atmosphere and time of exposure and is a concern when the molar fraction of oxygen is increased, as in nitrox diving. The effect of carbon dioxide changes from a respiration stimulant at normal partial pressures of 15-40 mmHg to a respiration suppressor above 80 mmHg.
The trick of just increasing O2 concentrations in the breathing liquid to elevate partial pressure gradients cannot be similarly applied to CO2 because the diver cannot tolerate much elevated CO2 levels in blood. Thus, the seeming dead end of liquid breathing research has been the inability to dispose of sufficient CO2 through the liquid filled, even when mechanically assisted, tidally breathed lungs. Partial liquid breathing combined with Extracorporeal Membrane Oxygenation (ECMO) has demonstrated some clinical promise; hence, my interest in exploring the possibility of an artificial gill for CO2 removal during deep diving with liquid breathing. Similar to a fish's gills, a membrane oxygenator-like artificial gill is a flow-through device, rather than a tidal device with. Given sufficient one-way flows of ambient water or a heat preserving closed circuit decarbonated breathing liquid, considerable CO2 removal can be expected. ECMO for CO2 removal during gentle, lung preserving one way insufflation of humidified O2 down the trachea, has demonstrated that only about ⅕ of cardiac output needs to be diverted extracorporeally in order to fully achieve the goal of proportionally dispelling CO2 (Kolobow, T., Gattinini., Tomlinson, T., Pierce,: Control of breathing using an extracorporeal membrane lung. Anesthesiology 46:138, 1977).
A trained athlete diver with cardiac output of 25 lpm would require the diversion of only 5 liters of femoral artery to femoral vein flow, a proportion easily acquired by modern percutaneous cannulation techniques. Oxygenation might also be not insignificantly aided, and silicone rubber membranes are not subject to O2 burn. Thus, interest in complementing the past efforts on liquid breathing with an artificial gill for CO2 removal seems warranted.
Liquid breathing has fascinated a number of researchers and a great deal of money has been spent on attempting to make it a viable, bends free, method for deep diving. (Lundgren C E Ornhagen H C. “Oxygen consumption in liquid breathing mice,” Aerosp Med (1972 August) 43(8):831-5) (Lynch P R Wilson J S Shaffer T H Cohen N. “Decompression incidence in air- and liquid-breathing hamsters.” Undersea Biomed Res (1983 March) 10(1):1-10).
Johannes Kylstra at the University of Buffalo, the most prolific researcher of liquid breathing in the 1960's, already recognized that the insufficiency of CO2 removal could not be similarly overcome by just increasing the dissolved gas pressure differential. Kylstra's hamsters survived huge pressure bounces lasting a few seconds and seemingly were not effected (Kylstra J A “Liquid breathing.” Undersea Biomed Res 1974 September 1(3):259-69).
Leland C. Clark and Frank Gollen at the University of Cincinnati, later in the 60's, came upon Fluorocarbon liquids as excellent carriers of O2 gas, and these liquids have been the strong hand of clinical liquid breathing ever since. Alliance Pharmaceutical's “Liquivent” stands out (Gollan F Clark L C, “Prevention of bends by breathing an organic liquid,” Trans Assoc Am Physicians (1967) 80:102-10) (Gollan F Clark L C. “Rapid decompression of mice breathing fluorocarbon liquid at 500 PSI,” Ala J Med Sci (1967 July) 4(3):336-7).
Moskowitz early recognized the need for mechanical means to relieve the effort required to tidally breathe heavy liquids. Clinicians caring for patients with underdeveloped or threatened lungs have made most use of these technologies at normal, ambient pressures (Moskowitz G D. “A mechanical respirator for control of liquid breathing,” Fed Proc 1970 September-October 29(5) (Moskowitz G D, Dubin S, Shaffer T H “Technical report: demand regulated control of a liquid breathing system,” J Assoc Adv Med Instrum 1971 September-October 5(5):273-8).
The artificial gill as an adjunct to liquid breathing, specifically to remove CO2, does not appear to have been recognized during the early heyday of hopes for liquid breathing in diving. Recently, the impressive works of Gattinoni and Kolobow and others utilizing a membrane oxygenator specifically for CO2 removal during lung preserving minimally breathing one-way O2 insufflation down the windpipe and ECMO appears to point to a resolution of the lingering CO2 problem of liquid breathing deep diving
Artificial Gill for Oxygen Scavenging
The artificial gill has been dreamed of since time immemorial and since the advent of efficient semipermeable membranes, has been imagined by many as well. Especially since the early days of membrane blood oxygenator development, numerous researchers proposed laying down membrane with seawater on one side and the diver's breathing on the other. Unfortunately, without some means for concentrating the O2, this has not led to any practical result (Ayres, A. W. Gill-type underwater breathing equipment and methods for reoxygenating exhaled breath, U.S. Pat. No. 3,228,394, (1966), Bodell, B. R. An Artificial Gill, Surgical Forum 16 (1965) 173-175), Cussler earlier demonstrated that thin silicone membranes could transfer sufficient gas to support the family dog for a short period of time (Yang, M C, Cussler E L Artificial Gills J. Membr. Sci 42 (1989) 273-284).
Other researchers have taken a very different tack which would include some form of considerable energy expenditure to try to express O2 out of the water: Joseph and Celia Bonaventura of Duke University foamed Hgb with polyurethane and produced a sponge that could attach O2 and later release it on demand, triggered by changes in temperature. They also demonstrated similar attach-and-release capacities for a number of O2 carriers upon the application of electricity. This latter technology is being utilized by their licensee, Aquanautics of Emeryville, Calif., for DARPA work supplying fuel cell powered submersibles.
The sequenced membranes and Hgb circuits arrangement of the present invention is therefore unique in being able to harness universal physiologic principles to carry out both oxygen scavenging and concentration to levels that are useful for a human diver or climber. The present invention also affords a means for dispelling CO2, which fulfills the promise of liquid breathing to permit deep diving without the bends. There is no prior gill work in either of these deep diving or oxygen scavenging areas by anyone, but the use of membrane oxygenators by Gattinoni and Kolobow, principally for dispelling CO2 during gentle, lung preserving clinical O2 insufflation down the trachea, provides an inspiration for this gill work.
Our oxygen scavenging diving technology might be totally integrated with our deep diving technology, where an artificial gill is attached to the A/V bloodstream principally to remove CO2. The artificial gill subsequently discharges that CO2 into the effluent from the liquid respirator and on toward the synthetic gill, where the CO2 laden PFC breathing liquid initiates and sustains the O2 scavenging function of the synthetic gill, which, in turn supplies the liquid breathing respirator with concentrated O2. Another area of interest is the development of nano-engineered membranes, which might make it possible to design the artificial gill much, much smaller (Infoscitex, Waltham, Mass., Personal Communication).
High Pressure Nervous Syndrome (HPNS) poses an additional threat to extreme deep diving, with convulsions threatening at different depths for different individuals. Research on HPNS has been muddied by the presence of concentrated diving gases and it is not clear, what are the effects of the gases verses what are the effects of pressure. The artificial gill for deep diving complementing liquid breathing will provide an excellent experimental platform for further understanding HPNS, without interference from diving gases. Lacking a system for bends free deep diving, considerable progress has been made utilizing submersible robots, but the potential value of a free swimming diver for accomplishing some vital tasks nevertheless remains.
Paracorporeal Artificial Lung
Current oxygenators that are the precursors for artificial gills largely have low resistance-to-flow paths only on one side of the membranes. Since the mid 1980's, most clinical oxygenators have been constructed from fine bore, microporous, hollow fibers with low viscosity O2 or mixed gas flowing through the fiber lumens and blood flowing around the outside wall in a largely counter and cross current direction.
It is believed that this flow arrangement was selected partly for economic reasons based on the easy availability of fibers and the generally short time, high flow and fully anticoagulated conditions of open heart surgery. Hemolysis was also noted while forcing blood through relatively narrow fibers (see below). However, researchers now pursuing the ideal oxygenator for prolonged ECMO or for continuing support with a paracorporeal artificial lung have been perplexed by uneven blood distribution, precipitation and even clotting and embolization at the lower flow rates and lesser anticoagulation that is practiced in a long term patient (Zwischenberger, J. B, personal communication.). The flat plate Landé-Lillehei experimental membrane oxygenator and the clinical Landé-Edwards units of about 1970, 30,000 of which were produced, had low flow resistances on both sides of the membrane but, alas, they have long been out of production. This call, and claims, for a gill-oxygenator with low resistances to flow on both sides of the membranes is thus relevant and can easily be met by the claimed hollow fibers with increased internal diameters, compared with the norm used in heart/lung machines used in cardiac surgery.
Others are working on silicone hollow fiber membranes for oxygenators that with larger lumens would make our gills much more blood friendly. Montoya at MC-3 in Ann Arbor appears to be embarked on such a development, using a “lost wax” method, layering silicone over water soluble mandrills. (U.S. Pat. No. 6,797,212-Method for forming hollow fiber). Also, Yukihiko Nose' at Baylor College of Medicine in Houston, in concert with Fuji Systems in Tokyo, is developing silicone hollow fiber membranes. (“Development of a new silicone membrane oxygenator for ECMO”, Ann Thorac. Cardiovas. Surg., 2000 December; 6(6):373-7)
Surgeon's and industry's current preference for generously anticoagulated blood in oxygenators flowing around microporous small diameter hollow fibers, rather than through them, stems in part from the high resistance that accompanied 5 l/min total bypass using the early 1980's Bentley Bos CM50, blood flow through the fibers device, which resulted in hemolysis. By contrast, kidney dialyzers (500 ml/min) have persisted in successfully using the blood flow through the fibers design. Importantly, CO2 removing oxygenators for ECMO as well as paracorporeal artificial lungs are required to process only ⅕ cardiac output (about 1 lpm). Diver's gills might require 1-5 lpm, depending on the level of activity. And long term support of patients as well as working divers and climbers will benefit from the simplified logistics of low resistance, arteriovenous or even pulmonary artery to pulmonary vein flows, whether pump free or pumped minimally. Such prolonged, marginally anticoagulated low flow support will also benefit greatly from the precisely defined flow paths for blood through identical large lumen, low resistance, parallel fibers, as opposed to the chaotic or stagnant paths of blood flowing around the fibers of current devices which results in clot formation and embolism. Unfortunately, both physicians and industry still suffer from the assumptions of short, high flow surgical bypass, while confronting the very different realities of low flow long-term support.
2. Oxygen Scavenging Synthetic Gill
While many researchers have jumped on the idea that all that is needed to breathe underwater would be to provide sufficient permeable membrane, Walter L. Robb, at General Electric, actually created a thin silicone membrane in the 1960's and publicized hamsters living in a box submerged in a fishbowl (U.S. Pat. No. 3,656,276). Cussler earlier demonstrated that thin silicone membranes could transfer sufficient gas to support the family dog for a period of time (Yang, M C, Cussler E L, Artificial Gills J. Membr. Sci 42 (1989) 273-284). However, most have realized that the O2 dissolved in seawater is so sparse that mere diffusion down concentration gradients would never suffice to support a human. The United States Army in 2005 requested proposals for a “synthetic gill”, both for diving and for high altitudes, which request made mention of hemoglobin and of swim bladders. It seemed that the Army thought both were of interest for O2 scavenging and storage, but little more guidance was provided. The awardee, INFOSCITEX, along with Case Western Reserve University, proposed to utilize nanotechnology to create a more gill-like membrane with several tiers of nano complexity. Little thought had or has been given to simple mechanisms that might be required to concentrate O2, rather most such thought has been directed toward complex mechanisms that require high levels of energy. (Bonaventure, J and Bonaventura, C., U.S. Pat. No. 4,761,209; Bodner, A., U.S. Pat. No. 7,278,422 licensed by Aquanautics, Emeryville, Calif.).
My interest was peaked by the thought that the unique capacities of Hgb might be harnessed to not only gather, transport, store and deliver O22 as in most living organisms, but that these capacities might also be utilized to concentrate O2 sequentially, with a result that might be compatible with sustaining a war fighter submerged in the shallows or at high altitude in rarefied O2. Referring to FIG. 8, that schematically shows my synthetic gill concept, a very large flow of seawater containing sparse O2, but with O2 at a partial pressure roughly equivalent to the air above (20% O2, 80% N2, distribution) is pumped or swim propelled close aboard the near (left) side of a very large about 40 square meters surface area semipermeable membrane. With the water so close, dissolved O2 will be drawn across the membrane, down concentration gradients, if an O2 sink is created on the far (right) side of the membrane. Such a sink results from CO2 permeating toward the near side, as per the physiologic Bohr Effect, as well as, to a lesser extent, by physical CO2 gradients, both leaving the far side Hgb, close to the membrane, alkaline and thus avid to attach 4 molecules of O2 per molecule of Hgb.